The objective of this R01 application is to develop and evaluate a high-resolution X-ray phase- contrast (XPC) imaging system and associated image reconstruction algorithms for in-vivo volumetric imaging of biomaterials in small animal models. The need for improved imaging methods for evaluating and monitoring biomaterials for tissue engineering/regeneration, drug delivery, and cell therapies applications is great. The ideal method would provide 3D quantitative information, possess high spatial resolution (<100 m), allow deep tissue penetration (>5 cm), and provide contrast between tissue and material structures essential for evaluating tissue response and development. Currently available imaging methods fall short in one or more of these requirements and this is currently limiting the development of biomaterial-based therapies. Moreover, these limitations hinder a variety of other preclinical imaging applications. For high-resolution applications of XPC, a microfocus X-ray tube is required in combination with a magnification geometry. Although kW power tubes equipped with source gratings are being actively explored for XPC imaging using a Talbot-Lau interferometer, that implementation does not meet the resolution requirements needed for monitoring biomaterials in small animal models and many other preclinical applications. Despite significant effort devoted in recent years to the development of XPC computed tomography (CT) using tube-based sources, the technology is still plagued by long data-acquisition times and relatively high radiation doses. Accordingly, the technology is not yet suitable for routine live animal imaging. The dominant cause of the long acquisition times in high-resolution implementations of XPC CT is the brightness limitations of conventional microfocus tubes set by the melting point of the anode target material. Another important contributing factor is that the advantages of optimized tomosynthesis data-acquisition strategies coupled with advanced statistically principled image reconstruction methods have not been fully exploited. The proposed research directly addresses the current limitations of high-resolution XPC imaging and will permit its translation for in-vivo volumetric imaging of biomaterials in small animal models. Our approach involves a high degree of innovation regarding both the hardware implementation and image reconstruction methods. The specific aims of the project are as follows. Aim 1: Develop and characterize an XPC tomosynthesis imager based on a MetalJet source for 3D monitoring of biomaterials; Aim 2: Develop advanced image reconstruction algorithms to maximize image quality; Aim 3: Refine the imaging system via computer-simulations and imaging experiments; Aim 4: Validate XPC imaging for in-vivo volumetric imaging of biomaterials in pre-clinical animal models.